Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations

Fang Wang, Xia-Yao Diao, Xiao Zhang, Qiong Shao, Yan-Fen Feng, Xin An, Hai-Yun Wang, Fang Wang, Xia-Yao Diao, Xiao Zhang, Qiong Shao, Yan-Fen Feng, Xin An, Hai-Yun Wang

Abstract

Background: Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations.

Methods: We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS.

Results: Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor.

Conclusions: We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

Keywords: Epidermal growth factor receptor; Non-small-cell lung cancer; Resistance; Tyrosine kinase inhibitors.

Figures

Fig. 1
Fig. 1
Kaplan-Meier curves of the progression-free survival (PFS) and overall survival (OS) for NSCLC patients with EGFR signaling pathway alterations. PFS (a) and OS (b) were analyzed in the 416 NSCLC patients, according to the EGFR signaling pathway alterations. In the 156 NSCLC patients with EGFR mutation, PFS (c) and OS (d) were analyzed according to the EGFR signaling pathway alterations. The survival rates were compared using the log-rank test. NSCLC non-small cell lung cancer, PFS progression-free survival, OS overall survival
Fig. 2
Fig. 2
Kaplan-Meier curves of the progression-free survival (PFS) and overall survival (OS) for NSCLC patients with RG alterations. PFS (a) and OS (b) were analyzed in the 416 NSCLC patients, according to the RG alterations. In the subgroups of NSCLC patients that were EGFR+/RG−, EGFR+/RG+, EGFR−, PFS (c) and OS (d) were analyzed. The survival rates were compared using the log-rank test. NSCLC non-small cell lung cancer, PFS progression-free survival, OS overall survival, RG resistance gene
Fig. 3
Fig. 3
Kaplan-Meier curves of the progression-free survival (PFS) and overall survival (OS) for mutant-EGFR NSCLC patients with aberrations in PTEN and MET genes. PFS (a) and OS (b) were analyzed in the 169 EGFR-mutant NSCLC patients, according to PTEN copy number alterations. In the subgroups of EGFR-mutant NSCLC patients with MET FISH status, PFS (c) and OS (d) were analyzed. The survival rates were compared using the log-rank test

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